Changes In Lipoprotein Lipase Research Articles

Changes in Lipoprotein Lipase in the Heart Following Diabetes Onset

Due to its constant pumping and contraction, the heart requires a substantial amount of energy, with fatty acids (FAs) providing a major part of its adenosine triphosphate (ATP). However, the heart is incapable of making this substrate and attains its FAs from multiple sources, including the action of lipoprotein lipase (LPL). LPL is produced in cardiomyocytes and subsequently secreted to its heparan sulfate proteoglycan (HSPG) binding sites on the plasma membrane. To then move LPL to the endothelial cell (EC) lumen, glycosylphosphatidylinositol-anchored high-density lipoprotein-binding protein 1 (GPIHBP1) attaches to interstitial LPL and transfers it to the vascular lumen, where the LPL is ready to perform its function of breaking down circulating triglycerides (TG) into FAs. The endo-β-glucuronidase heparanase (Hpa) is unique in that it is the only known mammalian enzyme to cleave heparan sulfate (HS), thereby promoting the abovementioned release of LPL from the cardiomyocyte HSPG. In diabetes, it has been suggested that changes in how the heart generates energy are responsible for the development of diabetic cardiomyopathy (DCM). Following moderate diabetes, with the reduction in glucose utilization, the heart increases its LPL activity at the vascular lumen due to an increase in Hpa action. Although this adaptation might be beneficial to compensate for the underutilization of glucose by the heart, it is toxic over the long term, as harmful lipid metabolite accumulation, along with augmented FA oxidation and thus oxidative stress, leads to cell death. This coincides with the loss of a cardioprotective growth factor—namely, vascular endothelial growth factor B (VEGFB). This review discusses interconnections between Hpa, LPL, and VEGFB and their potential implications in DCM. Given that mechanism-based therapeutic care for DCM is unavailable, understanding the pathology of this cardiomyopathy, along with the contribution of LPL, will help us advance its clinical management.

Heterozygous lipoprotein lipase knockout mice exhibit impaired hematopoietic stem/progenitor cell compartment.

BackgroundHematopoietic stem cells (HSC) maintain the hematopoietic system homeostasis through self‐renewal and multilineage differentiation potential. HSC are regulated by the microenvironment, cytokine signaling, and transcription factors. Recent results have shown that lipid pathways play a key role in the regulation of HSC quiescence, proliferation, and division. However, the mechanism by which lipid metabolism regulates HSC proliferation and differentiation remains to be clarified. Lipoprotein lipase (LPL) is an essential enzyme in the anabolism and catabolism of very low‐density lipoprotein, chylomicrons, and triglyceride‐rich lipoproteins.MethodsThe percentage of hematopoietic stem/progenitor cells and immune cells were determined by fluorescence‐activated cell sorting (FACS). The function and the mechanism of HSCs were analyzed by cell colony forming assay and qPCR analysis. The changes in LPL+/− HSC microenvironment were detected by transplantation assays using red fluorescent protein (RFP) transgenic mice.ResultsTo explore the function of LPL in HSC regulation, heterozygous LPL‐knockout mice (LPL+/−) were established and analyzed by FACS. LPL+/− mice displayed decreased hematopoietic stem/progenitor cell compartments. In vitro single‐cell clonogenic assays and cell‐cycle assays using FACS promoted the cell cycle and increased proliferation ability. qPCR analysis showed the expression of p57KIP2 and p21WAF1/CIP1 in LPL+/− mice was upregulated.ConclusionsLPL+/− mice exhibited HSC compartment impairment due to promotion of HSC proliferation, without any effects on the bone marrow (BM) microenvironment.

Distribution and variation in proteins of casein micellar fractions response to heat-treatment from five dairy species

Casein micelles (CMs) contribute to the physicochemical properties and stability of milk. However, how the proteome of CMs changes following heat treatment has not been elucidated. Here, changes in the proteins of CMs in samples of Holstein, buffalo, yak, goat, and camel milk following heat treatment were investigated using a LC-MS/MS approach. According to the hierarchical clustering results, Holstein, yak, and buffalo milk samples had similar CMs protein components, followed by goat and camel milk samples. Changes in lipoprotein lipase and α-lactalbumin in CMs were dependent on the intensity of heat treatment and were similar among the studied species, whereas changes in κ-casein, lactoferrin, and apolipoprotein A-I differed among different types of milk. These results provide information on the distribution and variations of the proteomes of CMs following heat treatment, which will assist in the identification of proteins that are dissociated and attached to CMs from different dairy species during heat treatment.

Lipoprotein Lipase and Its Delivery of Fatty Acids to the Heart.

Ninety percent of plasma fatty acids (FAs) are contained within lipoprotein-triglyceride, and lipoprotein lipase (LPL) is robustly expressed in the heart. Hence, LPL-mediated lipolysis of lipoproteins is suggested to be a key source of FAs for cardiac use. Lipoprotein clearance by LPL occurs at the apical surface of the endothelial cell lining of the coronary lumen. In the heart, the majority of LPL is produced in cardiomyocytes and subsequently is translocated to the apical luminal surface. Here, vascular LPL hydrolyzes lipoprotein-triglyceride to provide the heart with FAs for ATP generation. This article presents an overview of cardiac LPL, explains how the enzyme works, describes key molecules that regulate its activity and outlines how changes in LPL are brought about by physiological and pathological states such as fasting and diabetes, respectively.

The Angiopoietin-Like Protein 3 and 8 Complex Interacts with Lipoprotein Lipase and Induces LPL Cleavage.

Lipoprotein lipase (LPL) is the key enzyme that hydrolyzes triglycerides from triglyceride-rich lipoproteins. Angiopoietin-like proteins (ANGPTL) 3, 4, and 8 are well-characterized protein inhibitors of LPL. ANGPTL8 forms a complex with ANGPTL3, and the complex is a potent endogenous inhibitor of LPL. However, the nature of the structural interaction between ANGPTL3/8 and LPL is unknown. To probe the conformational changes in LPL induced by ANGPTL3/8, we found that HDX-MS detected significantly altered deuteration in the lid region, ApoC2 binding site, and furin cleavage region of LPL in the presence of ANGPTL3/8. Supporting this HDX structural evidence, we found that ANGPTL3/8 inhibits LPL enzymatic activities and increases LPL cleavage. ANGPTL3/8-induced effects on LPL activity and LPL cleavage are much stronger than those of ANGPTL3 or ANGPTL8 alone. ANGPTL3/8-mediated LPL cleavage is blocked by both an ANGPTL3 antibody and a furin inhibitor. Knock-down of furin expression by siRNA significantly reduced ANGPT3/8-induced cleavage of LPL. Our data suggest ANGPTL3/8 promotes furin-mediated LPL cleavage.

Effects of dietary fat source and green tea (Camellia sinensis) extract on genes associated with lipid metabolism and inflammatory responses in female broiler chickens

This study was aimed to investigate the effects of dietary fat sources and green tea extract (GTE) on gene expression associated with lipid metabolism and inflammation in broiler chicken. A total of 300 female Ross 308 broiler chicks were allocated to six dietary treatments in a completely randomised design with a factorial arrangement of two levels of GTE (0 and 500 mg/kg diet) × three levels of fat inclusion [without fat (control group), soybean oil (SO) and tallow (Ta)]. Liver fat (LF), liver methallothionin (LMT) content, and lipoprotein lipase (LPL), adipose triglyceride lipase (ATGL), tumour necrosis factor α (TNF-α), and interleukin (IL-6)] genes expression were investigated. Relative expression and statistical analyses of genes expression were assessed using REST software. The effect of added dietary fats was significant and improved performance parameters compared to the control group (p < .05). The highest abdominal fat and blood triglyceride, and the lowest carcase yield, were achieved in chicks fed SO-supplemented diet (p < .05). Chicks fed a diet supplemented with SO showed an overexpression and a decrease of LPL and ATGL compared to the Ta-supplemented and control groups, respectively (p < .05). GTE supplementation was effective on LPL and ATGL expression and ameliorated the effect of SO on abdominal fat percentage. TNF-α expression, LMT content, and relative weight of lymphoid organs were affected neither by GTE nor by the fat sources. There was no detection of IL-6 gene expression in adipose tissue. The results of this study demonstrated that diets rich in SO were capable increase fat deposition by an increase and decrease in LPL and ATGL gene expression, respectively. However inclusion of GTE in broiler diets alleviated the LPL-increasing and ATGL-reducing effects of SO and ameliorated the effect of SO on abdominal fat mass. Highlights Diets supplemented with SO increased abdominal fat mass by changes in LPL and ATGL gene expression. Obesity was not effective in the expression of inflammatory genes (TNF-α and IL-6), indicating a lack of connection between inflammation and obesity in broiler chicken. GTE (500 mg/kg diet) addition to the diets supplemented with SO ameliorated the effect of SO on LPL and ATGL gene expression and abdominal fat mass.

A novel long noncoding RNA, ENSGALG00000021686, regulates the intracellular transport of fatty acids by targeting the FABP3 gene in chicken

Fatty acids (FAs) are essential for the vital movement of humans and animals. Their metabolism is, in part, regulated by FABP3. In our previous study, a novel lncRNA (ENSGALG00000021686, L21686) was identified, and FABP3 was predicted as its target gene. Here, using chicken myocytes, lymphocytes, and different tissues, L21686 target on the FABP3 gene, FABP3 mRNA expression, and their effect on FA metabolism are explored. The results show that the highest expression of L21686 is in muscle tissue, a significant energy-consuming tissue. L21686 expression is consistent with FABP3 mRNA expression. We also show that under the different treatments, the levels of FABP3 mRNA and protein in myocytes and lymphocytes change in tandem with L21686 expression. Moreover, the dual-luciferase reporter assay provided direct evidence that L21686 targets the FABP3 gene. Finally, it was found that the content of free FAs increases along with the up-regulation of L21686 and the FABP3 gene. Malonyl CoA content does not change under the different treatments, suggesting that L21686 regulates the intake of extracellular FAs in chicken. Further, the changes in lipoprotein lipase (LPL), sterol-regulatory element binding protein 1 (SREBP-1), fatty acid synthase (FASN), and acetyl-CoA carboxylase (ACC) mRNA levels support this view. In summary, our data show that the new lncRNA (L21686) regulates the intake of extracellular FAs in chicken cells in vitro by targeting the expression of the FABP3 gene. Our findings will help to establish the groundwork and provide a new clue for deciphering the regulation of FAs metabolism in chicken.

Exercise with weight loss improves adipose tissue and skeletal muscle markers of fatty acid metabolism in postmenopausal women.

ObjectiveThe effects of six-months weight loss (WL) versus aerobic exercise training (AEX)+WL on fat and skeletal muscle markers of fatty acid metabolism were determined in normal (NGT) and impaired (IGT) glucose tolerant African-American and Caucasian postmenopausal women with overweight/obesity.MethodsFat (gluteal and abdominal) lipoprotein lipase (LPL), and skeletal muscle LPL, acyl-CoA synthase (ACS), β-hydroxacyl-CoA dehydrogenase, carnitine palmitoyltransferase (CPT-1), and citrate synthase (CS) activities were measured at baseline (n=104) and before and after WL (n=34) and AEX+WL (n=37).ResultsAfter controlling for age and race, muscle LPL and CPT-1 were lower in IGT, and the ratios of fat/muscle LPL activity were higher in IGT compared to NGT. Muscle LPL was related to insulin sensitivity (M), and inversely related to G120, fasting insulin, and HOMA-IR. AEX+WL decreased abdominal fat LPL and increased muscle LPL, ACS, and CS. The ratios of fat/muscle LPL decreased after AEX+WL. The change in VO2max was related to the changes in LPL, ACS, and CS and inversely related to the changes in fat/muscle LPL activity ratios.ConclusionsSix-month AEX+WL, and not WL alone, is capable of enhancing skeletal muscle fatty acid metabolism in postmenopausal African-American and Caucasian women with NGT, IGT, and overweight/obesity.

TNF-α decreases lipoprotein lipase activity in 3T3-L1 adipocytes by up-regulation of angiopoietin-like protein 4

Lipoprotein lipase (LPL) hydrolyzes lipids in plasma lipoproteins so that the fatty acids can be taken up and used by cells. The activity of LPL changes rapidly in response to changes in nutrition, physical activity and other conditions. Angiopoietin-like protein 4 (ANGPTL4) is an important controller of LPL activity. Both LPL and ANGPTL4 are produced and secreted by adipocytes. When the transcription blocker Actinomycin D was added to cultures of 3T3-L1 adipocytes, LPL activity in the medium increased several-fold. LPL mRNA decreased moderately during 5h, while ANGPTL4 mRNA and protein declined rapidly, explaining that LPL activity was increased. TNF-α is known to reduce LPL activity in adipose tissue. We have shown that TNF-α increased ANGPTL4 both at the mRNA and protein level. Expression of ANGPTL4 is known to be under control of Foxo1. Use of the Foxo1-specific inhibitor AS1842856, or knockdown of ANGPTL4 by RNAi, resulted in increased LPL activity in the medium. Both with ActD and with the Foxo1 inhibitor the cells became unresponsive to TNF-α. This study shows that TNF-α, by a Foxo1 dependent pathway, increases the transcription of ANGPTL4 which is secreted by the cells and causes inactivation of LPL.

SEDding Ourselves Up for Problems

SEDding Ourselves Up for Problems

Changes in activities and mRNA expression of lipoprotein lipase and fatty acid synthetase in large yellow croaker,Larimichthys crocea(Richardson), during fasting

Over-winter fasting and man-made food deprivation to increase meat quality are common in the process of large yellow croaker (Larimichthys crocea) aquaculture. This study aimed to determine the changes in lipoprotein lipase (LPL) and fatty acid synthetase (FAS) activities and mRNA expressions, and the relationships between these changes and fat content in large yellow croaker liver and muscle tissues during fasting. A total of 2933 bp LPL cDNA, including an open reading frame of 1533 bp encoding 510 amino acids, and a 1233 bp fragment of FAS cDNA coding 411 amino acids were cloned. Expressions of both genes were ubiquitous. During a 35-day fasting period, the hepatosomatic index and fat content in muscle and liver were significantly decreased (P < 0.05). mRNA levels of LPL increased significantly during the fasting period except the first 3 days, and FAS mRNA levels decreased significantly in both muscle and liver (P < 0.05) although there were some fluctuations. Muscle and liver LPL activities were significantly higher following fasting for 7 days, decreased to the initial value following fasting for 14 days, and elevating significantly afterwards (P < 0.05). FAS activities in muscle and liver maintained a significantly decreasing trend during the short-term fasting (P < 0.05) and kept obviously rising thereafter (P < 0.05). Activities and mRNA levels of both LPL and FAS were not always consistent, which implied that both pre-translational and post-translational regulations existed during fasting. Our results suggest that the reasonable fasting time is 21 days before harvesting when fat content decreased significantly.

Changes in lipoprotein lipase and endothelial lipase mass in familial hypercholesterolemia during three-drug lipid-lowering combination therapy.

BackgroundThis study was performed to compare the effects of three different lipid-lowering therapies (statins, ezetimibe, and colestimide) on lipoprotein lipase and endothelial lipase masses in pre-heparin plasma (pre-heparin LPL and EL mass, respectively) from patients with familial hypercholesterolemia (FH). FH is usually treated by coadministration of these three drugs.MethodsThe pre-heparin LPL and EL masses were measured in fresh frozen plasma drawn and stored at various time points during coadministration of the three drugs from patients with heterozygous FH harboring a single mutation in the LDL receptor (n = 16, mean age 63 years). The patients were randomly divided into two groups based on the timing when ezetimibe was added.ResultsPlasma LPL mass concentration was significantly reduced by rosuvastatin at 20 mg/day (median = 87.4 [IQR: 71.4–124.7] to 67.5 [IQR: 62.1–114.3] ng/ml, P < 0.05). In contrast, ezetimibe at 10 mg/day as well as colestimide at 3.62 g/day did not alter its level substantially (median = 67.5 [IQR: 62.1–114.3] to 70.2 [IQR: 58.3–106.2], and to 74.9 [IQR: 55.6–101.3] ng/ml, respectively) in the group starting with rosuvastatin followed by the addition of ezetimibe and colestimide. On the other hand, the magnitude in LPL mass reduction was lower in the group starting with ezetimibe at 10 mg/day before reaching the maximum dose of 20 mg/day of rosuvastatin. Plasma EL mass concentration was significantly increased by rosuvastatin at 20 mg/day (median = 278.8 [IQR: 186.7–288.7] to 297.0 [IQR: 266.2–300.2] ng/ml, P < 0.05), whereas other drugs did not significantly alter its level.ConclusionThe effects on changes of LPL and EL mass differed depending on the lipid-lowering therapy, which may impact the prevention of atherosclerosis differently.Electronic supplementary materialThe online version of this article (doi:10.1186/s12944-016-0238-z) contains supplementary material, which is available to authorized users.

Hepatic lipase gene -514C&gt;T variant is associated with exercise training-induced changes in VLDL and HDL by lipoprotein lipase

Our objective was to test the hypothesis that a common polymorphism in the hepatic lipase (HL) gene (LIPC -514C>T, rs1800588) influences aerobic exercise training-induced changes in TG, very-low-density lipoprotein (VLDL), and high-density lipoprotein (HDL) through genotype-specific increases in lipoprotein lipase (LPL) activity and that sex may affect these responses. Seventy-six sedentary overweight to obese men and women aged 50-75 yr at risk for coronary heart disease (CHD) underwent a 24-wk prospective study of the LIPC -514 genotype-specific effects of exercise training on lipoproteins measured enzymatically and by nuclear magnetic resonance, postheparin LPL and HL activities, body composition by dual energy x-ray absorptiometry and computer tomography scan, and aerobic capacity. CT genotype subjects had higher baseline total cholesterol, HDL-C, HDL(2)-C, large HDL, HDL particle size, and large LDL than CC homozygotes. Exercise training elicited genotype-specific decreases in VLDL-TG (-22 vs. +7%; P < 0.05; CC vs. CT, respectively), total VLDL and medium VLDL, and increases in HDL-C (7 vs. 4%; P < 0.03) and HDL(3)-C with significant genotype×sex interactions for the changes in HDL-C and HDL(3)-C (P values = 0.01-0.02). There were also genotype-specific changes in LPL (+23 vs. -6%; P < 0.05) and HL (+7 vs. -24%; P < 0.01) activities, with LPL increasing only in CC subjects (P < 0.006) and HL decreasing only in CT subjects (P < 0.007). Reductions in TG, VLDL-TG, large VLDL, and medium VLDL and increases in HDL(3)-C and small HDL particles correlated significantly with changes in LPL, but not HL, activity only in CC subjects. This suggests that the LIPC -514C>T variant significantly affects training-induced anti-atherogenic changes in VLDL-TG, VLDL particles, and HDL through an association with increased LPL activity in CC subjects, which could guide therapeutic strategies to reduce CHD risk.

Decreased Protein Expression of Lipoprotein Lipase in Late Fasting Elephant Seals

During prolonged food deprivation, glycogen stores are depleted, and mammals rely on oxidation of fatty acids for energy. Thus, the breakdown of triglycerides (TG) becomes a critical process by which metabolic substrates become available to support energy requirements. Prolonged fasting is associated with the onset of insulin resistance so it should be expected that content of insulin-responsive enzymes such as lipoprotein lipase (LpL) which cleave TG would decrease resulting in decreased free fatty acids (FFA) and glycerol. Prolonged fasting in northern elephant seals is associated with decreased insulin but elevated FFA; the changes in LpL have not been examined. To address the hypothesis that LpL decreases in fasting seals, we measured adipose LpL in Early (n=9; 2–3 weeks post weaning) and Late (n=8; 6–8 weeks post weaning) fasted pups. LpL decreased (8%), but plasma FFA, glycerol and TG all increased 41%, 27% and 40%, respectively late in fast. This suggests that LpL does not contribute significantly to metabolism of TG in adipose of prolong-fasted seals. Increased TG may be necessary to provide sufficient substrate for increased lipolysis, resulting in increased FFA and glycerol. This pattern of substrate-product utilization suggests elephant seals have a robust mechanism to maintain TG levels to maintain energetic demands during their fast. This project was funded by NIH NCMHD 9T37MD001480 & P20MD005049.

2008 Robert Levy Memorial Lecture—Tissue-Specific Regulation of Lipoprotein Lipase and Energy Balance: The Story Gets Even More Interesting

Lipoprotein lipase (LPL) is a multifunctional enzyme produced by and studied in many tissues, including adipose tissue, cardiac and skeletal muscle, islets, and macrophages. After synthesis by parenchymal cells, the lipase is transported to the capillary endothelium, where it is rate-limiting for the hydrolysis of the triglyceride (TG) core of the circulating TG-rich lipoproteins, chylomicrons, and very low density lipoproteins (VLDL). The reaction products, fatty acids and monoacylglycerol, are in part taken up by the tissues locally, where they are processed in a tissue-specific manner, e.g., stored as neutral lipids (TG &gt; cholesteryl esters[CE]) in adipose tissue, oxidized or stored in muscle, or as CE/TG in foam cells in macrophages. LPL is regulated in a tissue-specific manner. In adipose tissue, LPL is increased by insulin and meals but decreased by fasting, whereas muscle LPL is decreased by insulin and increased by fasting. In obesity, adipose tissue LPL is increased; however, the insulin dose-response curve is shifted to the right. After weight reduction and stabilization of the reduced obese state, adipose tissue LPL is increased, as is the response of the enzyme to insulin and meals. In skeletal muscle, insulin does not stimulate LPL nor is the enzyme activity changed in obesity; however, after weight reduction, LPL in skeletal muscle is decreased by 70%. These tissue-specific changes in LPL set the stage for lipid partitioning to help explain the recidivism of obesity. To examine this divergent regulation further, transgenic and knockout murine models of tissue-specific LPL expression have been developed. Mice with overexpression of LPL in skeletal muscle develop TG accumulation in muscle, develop insulin resistance, are protected from excessive weight gain, and increase their metabolic rate in the cold. When placed onto the LPL knockout and leptin deficient background, overexpression of LPL using an MCK promoter reduces obesity. Alternatively, a deletion of LPL in skeletal muscle reduces TG accumulation and increases insulin-mediated glucose transport into muscle but leads to lipid partitioning to other tissues, insulin resistance, and obesity. In the heart, loss of LPL is associated with hypertriglyceridemia and a greater utilization of glucose, implying that free fatty acids are not a sufficient fuel for optimal cardiac function. LPL is also produced in the brain, and that’s where the “story gets even more interesting.” We have just created mice with a neuron-specific deletion of LPL (NEXLPL−/−) using cre recombinase driven by the helix-loop-helix nuclear transcription factor NEX promoter. By 6 months of age, NEXLPL−/− mice weigh 50% more than their litter mates. This phenotype provides convincing evidence that lipoprotein sensing occurs in the brain and is important to energy balance and body weight regulation. Overall, LPL is a fascinating enzyme that contributes in a pronounced way to normal lipoprotein metabolism, tissue-specific substrate delivery and utilization, and to the many aspects of metabolism that relate to cardiovascular disease, including energy metabolism, insulin action, body weight regulation, and atherosclerosis.

Changes in lipoprotein lipase modulate tissue energy supply during stress

We studied the variations caused by stress in lipoprotein lipase (LPL) activity, LPL-mRNA, and local blood flow in LPL-rich tissues in the rat. Stress was produced by body immobilization (Immo): the rat's limbs were taped to metal mounts, and its head was placed in a plastic tube. Chronic stress (2 h daily of Immo) decreased total LPL activity in mesenteric and epididymal white adipose tissue (WAT) and was accompanied by a weight reduction of these tissues. In limb muscle, heart, and adrenals, total LPL activity and mRNA levels increased, and, in plasma, LPL activity and mass also increased. Acute stress (30-min Immo) caused a decrease in total LPL activity only in retroperitoneal WAT and an increase in preheparin plasma active LPL, but the overall weight of this tissue did not vary significantly. We propose an early release of the enzyme from this tissue into the bloodstream by some unknown extracellular pathways or other local mechanisms. These changes in this key energy-regulating enzyme are probably induced by catecholamines. They modify the flow of energy substrates between tissues, switching the WAT from importer to exporter of free fatty acids and favoring the uptake by muscle of circulating triacylglycerides for energy supply. Moreover, we found that acute stress almost doubled blood flow in all WAT studied, favoring the export of free fatty acids.

Cancer cachexia.

CAUSATIVE FACTORS: Nutritional supplementation or pharmacological manipulation of appetite are unable to control the muscle atrophy seen in cancer cachexia. This suggests that tumour and/or host factors might be responsible for the depression in protein synthesis and the increase in protein degradation. An increased expression of the ubiquitin-proteasome proteolytic pathway is responsible for the increased degradation of myofibrillar proteins in skeletal muscle, and this may be due to tumour factors, such as proteolysis-inducing factor (PIF), or host factors such as tumour necrosis factor-alpha (TNF-alpha). In humans loss of adipose tissue is due to an increase in lipolysis rather than a decrease in synthesis, and this may be due to tumour factors such as lipid-mobilising factor (LMF) or TNF-alpha, both of which can increase cyclic AMP in adipocytes, leading to activation of hormone-sensitive lipase (HSL). Levels of mRNA for HSL are elevated twofold in adipose tissue of cancer patients, while there are no changes in lipoprotein lipase (LPL), involved in extraction of fatty acids from plasma lipoproteins for storage. TREATMENT FOR CACHEXIA: This has concentrated on increasing food intake, although that alone is unable to reverse the metabolic changes. Agents interfering with TNF-alpha have not been very successful to date, although more research is required in that area. The only agent tested clinically that is able to interfere with the action of PIF is eicosapentaenoic acid (EPA). EPA attenuates protein degradation in skeletal muscle by preventing the increased expression of the ubiquitin-proteasome pathway, but has no effect on protein synthesis. When used alone EPA prevents further wasting in cachectic patients, and, when it is combined with an energy- and protein-dense nutritional supplement, weight gain is seen, which is totally lean body mass. These results suggest that mechanistic studies into the causes of cancer cachexia will allow appropriate therapeutic intervention.

Exercise training, without weight loss, increases insulin sensitivity and postheparin plasma lipase activity in previously sedentary adults.

To determine the effects of exercise, without weight loss, on insulin sensitivity (S(I)), postheparin plasma lipase activity (PHPL), intravenous fat clearance rate (K(2)), and fasting lipids in sedentary adults. At baseline and after 6 months of walk training (intensity 45-55 or 65-75% heart rate reserve, frequency 3-4 or 5-7 days/week, duration 30 min/session), anthropometric indexes, S(I), PHPL, K(2), and fasting lipids were measured in 18 sedentary adults (12 women, 6 men; 51.9 +/- 5.8 years of age, BMI 28.9 +/- 4.6 kg/m(2)). Exercise increased S(I) (2.54 +/- 2.74 vs. 4.41 +/- 3.30 microU ml(-1) x min(-1), P < 0.005) and both lipoprotein lipase (LPL) (1890 +/- 1380 vs. 4926 +/- 1858 nEq free fatty acid [FFA]. ml(-1). h(-1)) and hepatic lipase (HL) activities (3326 +/- 1605 vs. 4636 +/- 1636 nEq FFA. ml(-1) x h(-1)) (both P < 0.001), without altering BMI, waist circumference, K(2), or fasting lipids. Correlations between changes in LPL and the total:HDL cholesterol ratio (r = -0.54) and changes in the LPL:HL ratio and waist circumference (r = -0.50) were significant (P < 0.05). Exercise, without weight loss, increases S(I) and PHPL activity in previously sedentary adults, without changing K(2) or fasting lipid levels. Furthermore, increased LPL is associated with a decreased total:HDL ratio, and an increased LPL:HL ratio is associated with a decreased waist circumference. Therefore, even modest amounts of exercise in the absence of weight loss positively affect markers of glucose and fat metabolism in previously sedentary, middle-aged adults.

PPAR-γ, TNF-α Messenger RNA levels and lipase activity in the pregnant and lactating rat

Dramatic alternations in maternal metabolism occur during gestation and lactation, especially glucose and fat metabolism. For example, in rats, the amount of body fat mass increases during gestation, then decreases just prior to delivery, and remains low after parturition. To investigate the factors involved in such changes in maternal fat mass, messenger ribonucleic acid (mRNA) levels of adipocytokines, peroxisome proliferator-activated receptor-γ (PPAR-γ) and tumor necrosis factor-α (TNF-α), were examined in the intraabdominal adipose tissue of non-pregnant rats, pregnant rats and postpartum rats. We also examined the issue of whether apoptosis, which could be promoted by PPAR-γ and TNF-α, is involved in any of the changes in maternal fat mass The activity of lipoprotein lipase (LPL) and hormone sensitive lipase (HSL) in adipose tissue was also measured. PPAR-γ and TNF-α mRNA levels remained constant during the gestational and postpartum periods. Apoptosis was not detected at any time as evidenced by DNA laddering and in situ staining. LPL activity was significantly increased at day 5 and remained elevated until day 14 of gestation. HSL activity was significantly increased at day 10 of gestation and then decreased after delivery, at day 10 of lactation. In conclusion, during the gestational and postpartum period of rats, changes in maternal fat mass did not directly correlate with the levels of expression of PPAR-γ and TNF-α mRNA. Apoptosis also does not appear to influence on fat mass change. The changes in LPL and HSL activities during gestation suggest that these enzymes might be regulators of maternal adipose tissue level.

Effect of diet on adipose tissue and skeletal muscle VLDL receptor and LPL: implications for obesity and hyperlipidemia

This study was designed to examine the effect of a high-fat (primarily saturated), refined-carbohydrate (sucrose) diet (HFS), which is known to induce obesity and hyperlipidemia, on adipose tissue and skeletal muscle lipoprotein lipase (LPL) and very-low density lipoprotein receptor (VLDL-R) protein expressions. Female Fischer rats were placed on either a HFS or a low-fat, complex-carbohydrate (LFCC) diet for 22 months beginning at 2 months of age. After 20 months, a subgroup of the HFS rats were switched to the LFCC diet for 2 months (HFS/LFCC). Body weight, feed efficiency, plasma total cholesterol, VLDL-C, low-density lipoprotein cholesterol (LDL-C) and triglyceride (TG) concentrations and LDL-C to high-density lipoprotein cholesterol ratio were all significantly raised by the HFS diet and improved by conversion to the LFCC diet. Adipose tissue heparin-releasable, extractable and total LPL activity expressed per cell were significantly increased in the HFS-fed group. However, LPL protein abundance normalized against total cellular protein was unchanged in the HFS group. This observation is consistent with the presence of adipose tissue hypertrophy. Skeletal muscle LPL protein abundance and heparin-releasable activity were reduced by the HFS diet and improved after switching to the LFCC diet. Both adipose tissue and skeletal muscle VLDL-R protein levels were significantly reduced by the HFS diet and increased after conversion to the LFCC diet. We conclude that an HFS diet induces changes in LPL and VLDL-R in a manner which favors shunting of dietary fat from skeletal muscle to adipose tissue and decreases TG-rich lipoprotein clearance contributing to increased plasma lipids and obesity. Conversion to a LFCC diet can ameliorate the dyslipidemia and tissue changes induced by long-term HFS diet consumption.